We have developed an efficient methodology that allows the synthesis of pyrimidine derivatives with a high degree of molecular diversity. We have shown that easily available 2-thiouracils of type (2) can be used as versatile building blocks toward the preparation of substituted 4-alkoxypyrimidine (4) through a simple O-alkylation reaction. The steric effects have a remarkable influence over the regioselectivity of the reaction, both using alkyl halides in basic conditions and with alcohols under Mitsunobu conditions. Optionally, further suitable manipulations over the substituents at the 4-position would enhance the introduction of additional diversity. Finally, oxidation of the thioether moiety to the corresponding sulfone 6 and nucleophilic displacement by different nucleophiles would produce the corresponding highly molecular diverse pyrimidines of type (7). The methodology developed in solution has been, successfully, transferred to the solid support (benzyl bromide replaced by Merrifield resin). A small library of molecularly diverse 4-alkoxypyrimidines has been prepared in parallel on solid support. The final products, 2-amino-4-alkoxypyrimidines (7), have been obtained in good overall yields. The study of the nucleophilic ipso-substitution reaction in 4-isopropoxypyrimidines (5, R5 = (CH3)2CH) has been expanded using a wide variety of nucleophiles (N-, C- and O-). The cleavage of 4-isopropoxy group afforded a collection of 2,6-disubstituted 4(3H)-pyrimidinones (8) (Figure 1). The introduction of several &#61538;- and &#61543;-aminoalcohols at the position 2- on the pyrimidine ring and the subsequent intramolecular cyclisation afforded different imidazo- and pyrimido[1,2-a]pyrimidinones (9 and 10). Intramolecular cyclisation of 4(3H)-pyrimidininones (8, Nu = aminoalcohols) under Mitsunobu conditions, afforded a separable mixture of the regioisomeric compounds (9) and (10) (Figure 1). Cyclisation of 4-isopropoxypyrimidines (7, Nu = aminoalcohols) with H2SO4 yielded the regioisomers (9) as the only products. Fynally, a little collection of &#61537;-arylglycines linked to the pyrimidinone ring (11) (Figure 1) has been prepared using the Petasis reaction. Several pyrimidine derivatives have shown inhibitory activity against Mycobacterium tuberculosis.